Abstract

Objectives This study sought to investigate the relationship between the degree of microvascular dysfunction assessed by a dual-sensor guidewire (pressure and Doppler velocity) and left ventricular (LV) remodeling after successful primary percutaneous coronary intervention (PPCI) for a first anterior acute myocardial infarction (AMI).

Methods In 24 consecutive patients, the microvascular resistance index (MVRI) immediately after PPCI was calculated as the ratio of the mean distal pressure to average peak flow velocity during maximal hyperemia. Cardiac magnetic resonance was performed to determine LV volumes at baseline and 8-month follow-up. LV remodeling was defined as an increase in left ventricular end-diastolic volume (LVEDV) of ≥20%.

Results In patients with an MVRI greater than the median value of 2.96 mm Hg·cm−1·s, the LVEDV increased significantly from 117.1 ± 20.7 ml at baseline to 146.5 ± 21.4 ml (p = 0.006) at 8 months, whereas it did not change between baseline and 8 months (108.2 ± 21.2 ml vs. 111.6 ± 29.9 ml, p = 0.620) in patients with an MVRI ≤2.96 mm Hg·cm−1·s. LV remodeling was more frequent in the group with an MVRI >2.96 mm Hg·cm−1·s (64% vs. 15%, p = 0.033). Furthermore, there was a positive correlation between MVRI and the percentage of increase or decrease in LVEDV (r = 0.42, p = 0.042). Logistic regression analysis showed that MVRI was the strongest univariate predictor of LV remodeling. The best cutoff value of MVRI was 2.96 mm Hg·cm−1·s with a sensitivity of 78% and a specificity of 73%.

Primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction is the most effective reperfusion strategy and improves survival by limiting myocardial necrosis (1). Despite successful recanalization of the infarct-related artery, however, left ventricular (LV) remodeling after acute myocardial infarction (AMI) develops in a substantial proportion of patients due to impaired microvascular reperfusion (2–5). LV remodeling has been shown to be associated with the development of heart failure and worse long-term clinical outcomes (6). Although the extent of microvascular dysfunction (MVD) is an important determinant of LV remodeling (7,8), predicting LV remodeling in the acute setting of myocardial infarction remains difficult because of the known disparity between epicardial coronary blood flow and microvascular perfusion. We recently showed that microvascular resistance index (MVRI) measured by a dual-sensor (pressure and Doppler velocity) guidewire immediately after PPCI in patients with anterior AMI was a useful predictor of infarct size and the transmural extent of infarction assessed by contrast-enhanced cardiac magnetic resonance (CMR) (9). However, it is unclear whether this index at the time of AMI reperfusion has an impact on progressive LV dilation compared with widely used indexes of microvascular reperfusion, such as myocardial blush grade, ST-segment resolution, and so on.

The aim of this study was to investigate the relationship between MVRI at the time of reperfusion and LV remodeling with serial CMR imaging in patients successfully treated with PPCI for AMI.

Methods

Patient population

From July 2009 to July 2010, we enrolled consecutive 30 patients after successful PPCI for a first anterior AMI within 12 h from the onset of symptoms. The diagnosis of AMI was based on: 1) chest pain continuing for >30 min; 2) ST-segment elevation of ≥2 mm (0.2 mV) in at least 2 contiguous precordial leads; and 3) Thrombolysis In Myocardial Infarction (TIMI) flow grade of 0, 1, or 2 at the initial coronary angiography. Successful PPCI was defined as residual stenosis ≤30% of the culprit lesion with TIMI flow grade 3. We excluded patients with previous myocardial infarction, left main coronary artery disease (≥50% stenosis), renal insufficiency (serum creatinine >1.5 mg/dl), and cardiogenic shock. Patients were also excluded if the patient had absolute or relative contraindications to magnetic resonance examination, such as a pacemaker, atrial fibrillation, and claustrophobia and if the patient experienced any cardiac event during 8-month follow-up. All of the patients gave written informed consent for participation in this study. The study complied with the Declaration of Helsinki.

Study protocol

Cardiac catheterization was performed by a percutaneous femoral approach with a 6-F guiding catheter. All patients received oral aspirin (162 mg) and a bolus of heparin (100 U/kg) before the procedure, and additional heparin was given if the procedure lasted >90 min to maintain an activated clotting time ≥250 s. An intracoronary bolus injection of isosorbide dinitrate (1 to 2 mg) was administered to obtain a high-quality angiogram and before hemodynamic measurements. PPCI was performed by the standard manner according to clinical guidelines at the time of the procedure. After manual thrombus aspiration using an Export catheter (Medtronic, Tokyo, Japan), balloon angioplasty was performed, followed by bare-metal stent implantation. Except for 2 patients who had received ticlopidine for stroke prevention, all patients were given a clopidogrel loading dose of 300 mg immediately after PPCI. After coronary stenting, all patients received dual antiplatelet therapy with ticlopidine (200 mg/day) or clopidogrel (75 mg/day) and aspirin (100 mg/day) for at least 30 days, followed by aspirin alone indefinitely. Myocardial blush grade was determined from the final angiogram by 2 experienced interventional cardiologists (Y.I. and K.K.) blinded to the MVRI result, as described previously (10). The ST-segment resolution was evaluated on a 12-lead electrocardiogram recorded in the emergency department and 1 h after PPCI. The sum of ST-segment resolution was measured 60 ms after J point in leads I, aVL, and V1 to V6. The percentage of resolution of ST-segment elevation from before to after PPCI was calculated. Complete reperfusion was defined as ≥70% ST-segment resolution on electrocardiography (11). To determine peak values of creatine kinase and creatine kinase-myocardial band (CK-MB), blood samples were obtained on admission and serially every 3 h for the first 24 h after PPCI. CMR was performed 11 ± 3 days after the onset of AMI and at 8 months.

Hemodynamic measurements and data analysis

Aortic pressure (Pa) was measured through the guiding catheter. Immediately after PPCI, distal pressure (Pd), and flow velocity distal to the culprit site were measured simultaneously with a 0.014-inch dual-sensor guidewire (ComboWire, Volcano Therapeutics, Rancho Cordova, California), as reported previously (9). In brief, after the wire was calibrated, advanced through the catheter, and equal with the Pa in the catheter, it was placed at least 3 to 4 cm distal to the stented segment of the left anterior descending artery and manipulated until an optimal and stable velocity signal was obtained. The position of the tip of the wire was confirmed by fluoroscopy and angiography. Pa, Pd, instantaneous peak velocity, and electrocardiogram were obtained online at baseline and after induction of maximal hyperemia with 150 μg/kg/min of intravenous adenosine triphosphate via a central venous catheter (ComboMap Pressure and Flow System, Volcano Therapeutics). Twenty minutes after PPCI, all signals were digitally recorded on a personal computer for offline analysis by an independent investigator (M.K.) who was unaware of patient data. Fractional flow reserve was calculated by dividing the mean Pd by the mean Pa during maximal hyperemia. Coronary flow reserve (CFR) was calculated as the ratio of time-averaged peak hyperemic to baseline average peak flow velocity. In 3 consecutive cardiac cycles, the deceleration time of diastolic velocity (ms) was measured from phasic coronary flow velocity recording as previously described (12) and averaged for the mean value. MVRI was calculated as the ratio of the mean Pd to the average peak flow velocity during maximal hyperemia (9).

CMR protocol

All CMR examinations were performed with a 1.5-T magnetic resonance scanner (Intera Achieva, Philips Medical Systems, Best, the Netherlands) equipped with a 5-element cardiac phased-array coil for signal reception, as previously described (9,13). First, breath-hold cine steady-state free precession images with a time resolution of 35 ms were acquired. Next, a breath-hold 3-dimensional turbo gradient echo with inversion recovery was used to obtain the late enhanced images. Contiguous short-axis slices and representative long-axis slices of the left ventricle were obtained 10 min after intravenous injection of 0.1 mmol/kg gadolinium-diethylenetriamine pentaacetic acid (Magnevist, Schering AG, Berlin, Germany). Scan parameters were as follows: repetition time, 4.1 ms; echo time, 1.25 ms; flip angle, 15°; field of view, 350 × 350 mm; partial echo; matrix, 224 × 256; and spatial resolution, 1.56 × 2.24 × 10 mm3 reconstructed to 0.68 × 0.68 × 5 mm3. All images were gated to the electrocardiogram and acquired during breath-hold at end expiration. We optimized the inversion time (200 to 300 ms) to null the normal myocardium. No complications related to the CMR procedures occurred. All 24 patients studied tolerated the procedure well, and all CMR scans were analyzable.

CMR data analysis and definitions

All CMR data were analyzed by the consensus of 2 observers (T.T. and Y.O.) who were blinded to clinical and hemodynamic data using an offline work station (View Forum, Phillips, Best, the Netherlands). Using a 17-segment model as previously recommended by the American Heart Association (14), myocardial necrosis was defined as transmural if late enhancement extended to >75% of the myocardial wall thickness in at least 2 contiguous LV segments among 16 segments except the apex. After the total volume of enhanced tissue was determined, infarct size was expressed as a percentage of LV volume as follows: volume of enhanced tissue × 100 ÷ total volume of LV myocardium. Microvascular obstruction (MVO) was defined as any region of hypoenhancement within the hyperenhanced infarcted area on late enhanced images and was included in the calculation of total infarct size. The LV volumes were calculated by tracing the end-diastolic and end-systolic LV slice contours using the modified Simpson’s rule method. End-diastolic and end-systolic volumes were defined as the largest and the smallest LV cavity, respectively. Papillary muscles were excluded from the volume measurements. LV ejection fraction was calculated as: (left ventricular end-diastolic volume [LVEDV] − LV end-systolic volume) ÷ LVEDV. The change in the LVEDV was evaluated as the percentage of increase or decrease in LVEDV from baseline to 8 months in each patient. LV remodeling was defined as an increase in LVEDV of ≥20%.

Statistical analysis

All statistical analyses were performed with SPSS software for Windows version 11.0 (SPSS Inc., Chicago, Illinois). Data were expressed as mean ± SD or number (%). Categorical variables were compared by the chi-square or Fisher exact test, as appropriate. Continuous variables were compared with the use of an unpaired Student t test. The paired-samples Student t test was used to compare differences in LVEDV between baseline and 8-month follow-up. Pearson’s correlation coefficient (r) was calculated for the relationship between MVRI and the percentage of increase or decrease in LVEDV. A univariate logistic regression model was used to examine independent associations between LV remodeling, MVRI, other parameters of coronary microcirculation (CFR, diastolic deceleration time, myocardial blush grade, and ST-segment resolution), pre-infarction angina, collaterals, peak CK-MB, and CMR parameters (infarct size, transmural necrosis, MVO, baseline LVEDV, baseline LV end-systolic volume, and baseline LV ejection fraction). Unadjusted odds ratios with their 95% confidence intervals were computed. Receiver-operating characteristic curve analysis was performed to assess the best cutoff value of MVRI to predict LV remodeling, using Medcalc (Medcalc Software, Mariakerke, Belgium). The optimal cutoff value was defined as the value with the highest sum of sensitivity and specificity. Values of p < 0.05 were considered statistically significant.

Results

Study population

Two of 30 patients were excluded from the study because of exclusion criteria (cardiogenic shock and atrial fibrillation). One patient was hospitalized for heart failure at 2 months. One patient underwent percutaneous coronary intervention for a new lesion in the infarct-related artery because of unstable angina at 3 months. Therefore, these 2 patients were also excluded from the study. A further 2 patients were excluded from analysis for refusal of follow-up CMR. Finally, 24 patients were analyzed. The median MVRI value in these patients was 2.96 mm Hg·cm−1·s. According to this median value, patients were divided into 2 groups: >2.96 mm Hg·cm−1·s (n = 11) and ≤2.96 mm Hg·cm−1·s (n = 13).

Baseline characteristics

As summarized in Table 1, the groups had similar baseline characteristics. The time to reperfusion was not different between patients with high or low MVRI. There were also no significant differences with respect to the use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker or a beta-blocker between the 2 groups. However, peak CK and peak CK-MB were significantly higher in patients with a high MVRI compared with those with a low MVRI. Normal myocardial blush (grade ≥2) was observed in 3 patients (27%) in the group with an MVRI >2.96 mm Hg·cm−1·s and 8 patients (62%) in the group with an MVRI ≤2.96 mm Hg·cm−1·s. The rate of complete ST-segment resolution was lower in patients having values >2.96 mm Hg·cm−1·s (18% vs. 62%, p = 0.047).

CMR results

The CMR findings at baseline and 8 months are summarized in Table 3. At baseline, infarct size in the group with an MVRI >2.96 mm Hg·cm−1·s was significantly larger than that in the group with an MVRI ≤2.96 mm Hg·cm−1·s (30.2 ± 78.7% vs. 18.3 ± 12.7%, p = 0.016). This initial significant difference in infarct size between groups was maintained at 8 months (29.1 ± 9.8% vs. 18.0 ± 12.1%, p = 0.023). Even though there were no significant differences in LVEDV and LV end-systolic volume at baseline between the 2 groups, the LVEDV and LV end-systolic volume at 8 months were significantly greater in the group with an MVRI >2.96 mm Hg·cm−1·s. At baseline, there was significant lower LV ejection fraction in patients with an MVRI >2.96 mm Hg·cm−1·s compared with patients with an MVRI ≤2.96 mm Hg·cm−1·s, whereas no difference in LV ejection fraction after 8 months between the 2 groups was observed. At baseline, MVO was present in 7 (64%) of 11 patients with a high MVRI and in 2 (15%) of 13 patients with a low MVRI (p = 0.033); no patients demonstrated MVO at follow-up. The incidence of transmural necrosis was not different between groups.

After thrombectomy, an obstructed lesion in the proximal left anterior descending artery was treated successfully with stenting. The time to reperfusion was 157 min. MVRI showed a high value of 3.36 mm Hg·cm−1·s. The LVEDV increased progressively from 113.4 ml to 194.8 ml, with % Δ LVEDV of 72%. Abbreviations as in Figures 1, 3, and 4.

Predictor of LV remodeling

On univariate analysis, MVRI measured immediately after PPCI was the only independent predictor of the development of LV remodeling at follow-up (odds ratio: 7.15; 95% confidence interval [CI]: 1.20 to 42.6; p = 0.031) (Table 4). Receiver-operating characteristic curve analysis for MVRI showed an area under the curve of 0.79 (95% CI: 0.57 to 0.93) (Fig. 6). The best cutoff value was found to be 2.96 mm Hg·cm−1·s. The sensitivity, specificity, and predictive accuracy were 78%, 73%, and 75%, respectively.

Receiver-operating characteristic curve analysis shows an area under the curve (AUC) of 0.79 (95% confidence interval [CI]: 0.57 to 0.93) and a 2.96-mm Hg·cm−1·s cutoff with a sensitivity of 78% and a specificity of 73% (red dot). Abbreviations as in Figure 1.

Univariate Logistic Regression Analysis for Predictors of Left Ventricular Remodeling

Discussion

The main findings of this study were as follows: 1) LV remodeling occurred in 38% of patients with a first anterior wall AMI despite early restoration of TIMI flow grade 3; 2) a high MVRI at the time of reperfusion was associated with the development of LV remodeling at 8 months; and 3) compared with other techniques for assessing MVD, such as myocardial blush grade, ST-segment resolution, CFR, diastolic deceleration time, and MVO, the degree of MVD assessed by MVRI was the only significant independent predictor of LV remodeling.

Although the pathophysiological mechanisms of post-infarction LV remodeling are multifactorial, the degree of perfusion of the infarct-related artery is a major determinant of LV volume change. Only patients with TIMI flow 3 grade have been considered as having successful epicardial perfusion (15). Despite successful recanalization of TIMI flow grade 3 in the infarct-related artery, however, LV remodeling can occur in 20% to 32% of patients after AMI; inadequate microvascular reperfusion is strongly associated with a higher rate of LV remodeling (2–5). In the present study, 38% of the entire study population experienced adverse LV remodeling at 8 months. This rate is somewhat high compared with the results of previous studies. This discrepancy may be explained partly by the difference in the performance of imaging modalities used (CMR vs. 2-dimensional echocardiography) to assess the change in LV volumes. CMR is currently considered the gold standard for assessment of LV volumes (16), and its accuracy and high reproducibility make this technique ideal for serial assessment of LV remodeling (17,18). Another explanation could be that our study included only patients with anterior AMI undergoing PPCI to the left anterior descending artery. However, when the results of MVRI measurement were taken into account, progressive LV dilation was significantly higher in patients with a high MVRI (64%) than in those with a low MVRI (15%). These rates of LV remodeling are in good agreement with those reported by Bolognese et al. (4). They used intracoronary myocardial contrast echocardiography to assess the extent of MVD in 124 patients with a TIMI flow grade 3 after PPCI. As a result, LV remodeling was observed in 63% of patients with MVD and 11% of patients without MVD, respectively. This finding supports the concept that MVRI may have the potential to distinguish patients in whom LV remodeling develops from those in whom it does not.

A number of invasive and noninvasive techniques have been proposed as methods for assessing the presence of impaired microvascular perfusion in the setting of AMI. Previous studies reported that myocardial blush grade and ST-segment resolution provided important information about LV dilation process beyond the standard TIMI flow grading (5,19). Garot et al. (3) reported that CFR assessed early after reperfusion by using a Doppler guidewire was a good predictor of LV remodeling. It has also been demonstrated that the coronary flow velocity pattern, including diastolic deceleration time, immediately after PPCI can predict LV dilation (20). In addition, MVO on CMR was recently shown to predict LV remodeling (21,22). However, as shown in this study, their predictive values in the prediction of post-infarction LV remodeling were definitely low compared with MVRI.

Study limitations

First, this study is limited by its small sample size. Second, pre-infarction angina was frequent in the low MVRI group (38% vs. 9%, p = 0.166). Therefore, the possibility that this may have had an influence on the prevalence of LV remodeling and hemodynamic measurements through recruitment of collaterals or ischemic preconditioning of the myocardium cannot be excluded necessarily. Third, because the size and extent of MVO were not evaluated in the present study, we may have underestimated the full potential of MVO to predict LV remodeling. Fourth, infarct size, which is predictive of the development of LV dilation (23), was significantly larger in patients with a high MVRI. However, there were no significant differences in baseline infarct size by CMR (27.9 ± 7.4% vs. 22.5 ± 14.3%, p = 0.305) and peak CK-MB (421 ± 197 IU/l vs. 287 ± 207 IU/l, p = 0.132) between patients with or without LV remodeling. Fifth, in calculating MVRI, we used only distal coronary pressure instead of the pressure gradient across the microvasculature by subtracting central venous pressure from distal coronary pressure. Therefore, the MVRI measured may have been falsely greater than when central venous pressure had been taken into consideration. Finally, although we measured coronary pressure and flow velocity 20 min after the last balloon inflation, previous animal studies demonstrated that the hyperemic reaction after the recanalization of occluded coronary arteries may continue for several hours (24,25), which may have affected our results.

Clinical implications

Even in the reperfusion era, LV remodeling remains an important treatment target. Measuring MVRI at the time of reperfusion may allow us to determine patients who may benefit from cell therapy to promote myocardial repair (26) or adjunctive pharmacological intervention to induce reverse remodeling (27).

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